This invention relates to methods that are useful in the prophylactic and affirmative treatment of pulmonary bacterial infection or symptomatic pulmonary exposure to endotoxin by inhalation of antiendotoxin compounds.
The incidence of gram-negative bacteremia in the United States has been estimated to be approximately 100,000 to 300,000 cases per year, with a mortality rate of 30-60%. Antibiotics are commonly used as the primary chemotherapy for this disease; however, their bactericidal action can result in disruption of the bacterium and concomitant release of endotoxin, i.e., the lipopolysaccharide (LPS) moiety of the bacterial outer membrane. The liberated LPS induces a number of pathophysiological events in mammals (collectively referred to as gram-negative endotoxemia or sepsis syndrome). These include fever, generalized inflammation, disseminated intravascular coagulation (DIC), hypotension, acute renal failure, acute respiratory distress syndrome (ARDS), hepatocellular destruction, and cardiac failure.
Although endotoxin initiates septic shock, it has little or no direct toxic effect on tissues; instead, it triggers an immunobiological response leading to a cascade of release of cytokines, such as tumor-necrosis factor (TNF), interleukin-1, interleukin-6, and interleukin-8, and other biological mediators, such as nitric oxide, as well as an array of secondary mediators (e.g., prostaglandins, leukotrienes, interferons, platelet-activating factor, endorphins, and colony-stimulating factors). Generation of pathophysiological concentrations of these cytokines and inflammatory mediators influences vasomotor tone, microvascular permeability, and the aggregation of leukocytes and platelets, causing a syndrome termed xe2x80x9csystemic inflammatory response syndromexe2x80x9d (or SIRS) and septic shock.
The bacterial lipopolysaccharide molecule has three main regions: a long chain polysaccharide (O Antigen), a core region, and a Lipid A region. The entire lipopolysaccharide molecule, as well as some of its individual components, possess toxic effects, as is described above. Most of these toxic effects, however, are believed to be attributable to the Lipid A portion. Structurally, Lipid A is composed of a diphosphorylated disaccharide, acylated by long chain fatty acids.
Therapies for endotoxin-related diseases have generally been directed towards controlling the inflammatory response. Such therapies include corticosteriod treatment, suggested to ameliorate endotoxin-mediated cell membrane injury and to reduce production of certain biological mediators; administration of antibodies designed to neutralize bacterial LPS; treatment with agents to suppress hypotension or with naloxone, which apparently blocks the hypotensive effects associated with sepsis syndrome; and treatment with nonsteroidal anti-inflammatory drugs, purported to block cyclooxygenanses and, thereby, decrease the production of certain secondary mediators, such as prostaglandins and thromboxane.
However, none of these therapies to date has resulted in significant reduction in the morbidity and mortality resulting from sepsis and septic shock syndrome. Thus, there is a long felt need for agents to affirmatively treat this disorder.
Christ et al., xe2x80x9cAnti-Endotoxin Compounds,xe2x80x9d U.S. Pat. No. 5,530,113, the contents of which are included by reference, disclose certain disaccharide compounds, such as B531, shown below, useful for the treatment of endotoxemia. 
Other references that disclose certain lipodisaccharides include Macher et al., Great Britain Patent No. 2,179, 945; Meyers et al., Great Britain Patent No. 2,220,211; Shiba et al., European Patent No. 172,581; Anderson et al., U.S. Pat. No. 4,495,346; and Shiba et al., U.S. Pat. No. 5,066,794.
The present invention is directed to the prevention and treatment of pulmonary bacterial infection or symptomatic pulmonary exposure to endotoxins and related disorders using liposaccharide analogs that are administered by inhalation. The compounds used in the present invention possess advantages for pharmaceutical use, such as enhanced pharmacological selectivity, efficacy, and, in particular, increased persistence of action. A representative compound of this invention, compound 1 (1287, SGEA), is shown below: 
Further, the present invention is directed to the prophylactic and affirmative treatment of any LPS-mediated disorder. These disorders include, but are not limited to, sepsis, septicemia (including but not limited to endotoxemia), endotoxemia resulting from gram-negative bacteremia (with its accompanying symptoms of fever, generalized inflammation, disseminated intravascular coagulation, hypotension, acute renal failure, acute respiratory distress syndrome, adult respiratory distress syndrome (ARDS), hepatocellular destruction and/or cardiac failure) and various forms of septic shock (including but not limited to endotoxic shock). Also, compounds of this invention will be useful in the prophylactic or affirmative treatment of localized or systemic inflammatory response to infection by different types of organisms, including gram-negative bacteria, and in diseases related to translocation of gram-negative bacteria or endotoxin from the gut. Together, these disorders are termed systemic inflammatory response syndrome or SIRS. (For a discussion of these terms, see Bone et al., Chest 101:1644-1655, 1992.)
Definitions
In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The term xe2x80x9calkylxe2x80x9d refers to aliphatic organic groups that may be branched or straight and which may be optionally substituted with one or more halogen atoms at any position along the alkyl chain. Alkyl groups include both groups that have a single unoccupied valence, for example, xe2x80x94CH2xe2x80x94CH3, and alkylene groups, which have two unoccupied valences, for example xe2x80x94CH2xe2x80x94CH2xe2x80x94. As is obvious to those skilled in the art, the single or double unoccupied valence will be used as appropriate to describe compounds that are chemically stable.
The term xe2x80x9cprodrugxe2x80x9d as used herein refers to any compound that has less intrinsic activity than the corresponding xe2x80x9cdrug,xe2x80x9d but when administered to a biological system, generates the xe2x80x9cdrugxe2x80x9d substance, either as a result of spontaneous chemical reaction or by enzyme catalyzed or metabolic reaction. Reference is made to various prodrugs, such as acyl esters, carbonates, phosphates, and urethanes, included herein as examples. The groups illustrated are exemplary, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs. Such prodrugs of the compounds of Formula I fall within the scope of the present invention.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d includes salts of compounds of Formula I derived from the combination of a compound of this invention and an organic or inorganic acid or base. The compounds of Formula I are useful in both non-ionized and salt form. In practice, the use of a salt form amounts to use of a base form; both forms are within the scope of the invention.
The term xe2x80x9cgeometric isomersxe2x80x9d refers to xe2x80x9ctransxe2x80x9d or xe2x80x9ccisxe2x80x9d (or xe2x80x9centgegenxe2x80x9d or xe2x80x9czusammenxe2x80x9d) isomers, as generally understood by those skilled in the art. All geometric isomers are within the scope of the invention.
Further, compounds of the present invention may contain asymmetric carbon atoms, and hence can exist as stereoisomers, both enantiomers and diastereomers. All stereoisomers and mixtures thereof are considered to fall within the scope of the present invention. The synthetic examples cited herein provide the most preferred isomer. It is evident that, in addition to the sugar moiety, additional asymmetric carbons may be present in compounds of Formula I, for example, in the side chains. In this event, all of the resulting diastereomers are considered to fall within the scope of the present invention.